A major project that involves the TIS is the definition of molecular biomarkers for autoimmune and autoinflammatory diseases. In collaboration with Dan Kastner and Ivona Aksentijevich at NHGRI, we have measured serum cytokines levels in patients with a novel autoinflammatory disease caused by mutations in the TRNT1 complex a tRNA processing enzyme. We found that proinflammatory cytokines - mainly interleukin (IL)-6, interferon gamma (IFN-) and IFN-induced cytokines - were elevated in the serum. Treatment with a TNF inhibitor suppressed inflammation, reduced the need for blood transfusions and improved growth in these patients. The results of this study have been published in Annals of Rheumatic Diseases. Furthermore, in collaboration with the Kastner and Kaplan groups we have been studying the deficiency of the complement component 1r which leads to early-onset systemic lupus erythematosus (SLE). Two siblings with SLE who were available for detailed evaluation exhibited strong type I interferon (IFN) inflammatory signatures despite their disease being clinically inactive at the time of sampling. The manuscript reporting these findings was published in Arthritis and Rheumatism. With the Goldbach-Mansky group at NIAID, we studied patients with Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated temperature (CANDLE), a Proteasome-Associated Autoinflammatory Syndrome (PRAAS), who were treated with the JAK inhibitor baricitinib. The TIS was responsible for measuring the STAT1 phosphorylation levels in leukocytes from these patients and correlate these to the pharmacokinetics of the drug. A manuscript reporting these findings was published in the Journal of Clinical Investigation. Furthermore, we were involved in two other studies that were associated with the same project. In one the TIS performed phosphoflow assays that confirmed the correlation of JAK inhibitor activity (measured as pSTATs) and the pharmacokinetics of baricitinib. These results were published in Clinical Pharmacology and Therapeutics. In the second one we reported the development and the validation of an Interferon score for patients with interferonopathies using the NanoString platform which was published in the Journal of Interferon and Cytokine Research. In collaboration with the Colbert group we have investigated the cytokine profile and the immunologic phenotype of a patient with a de-novo gain-of-function mutation in MyD88, which results in early-onset severe arthritis. A manuscript describing these results was published in the Journal of Allergy and Clinical Immunology. In support of the recently closed phase Ib clinical trial of a JAK inhibitor in SLE patients, the TIS has developed and validated a fluorescent barcoding protocol outlining an 8 color assay for the study of phospho-STATs signaling in peripheral blood mononuclear cells (PBMCs) obtained from the patients included in the study. The data are currently being analyzed. We have also extracted mRNA from samples obtained at different time points during the course of the trial and we are currently analyzing the transcriptome for each sample using RNAseq. The TIS has also been investigating novel approaches for the treatment of autoimmune diseases. In collaboration with the O'Shea group, the Kaplan group, and Pfizer (via a CRADA), we are currently evaluating the effects of tofacitinib and second-generation JAK-selective inhibitors on T cells and innate lymphoid cells.
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